We propose to test the hypothesis that mitochondrial dysfunction is an important factor in the etiology of autism spectrum disorders (ASD). The mitochondria play four central roles in cell and tissue function: they provide most of the energy, generate much of the reactive oxygen species (ROS), buffer cytosolic Ca++, and regulate cell death based on mitochondrial status. The mitochondrial genome is thought to encompass 1500 nuclear DNA (nDNA) genes and 37 mitochondrial DNA (mtDNA) genes. A comparative genomic hybridization (CGH) analysis of ASD lymphoblastoid cell line DNAs has revealed multiple copy number variants (CNVs) that impact nDNA mitochondrial genes, many CNVs being internal to the mitochondrial genes. Additional analyses have revealed mtDNA alterations. Since a partial mitochondrial oxidative phosphorylation (OXPHOS) defect is sufficient to generate neurological disease, these results suggest that mitochondrial dysfunction could account for a significant proportion of ASD. To further test this hypothesis we propose to: (1) expand our search for nDNA CNVs affecting mitochondrial genes in ASD lymphoblastoid cell lines, (2) analyze mtDNA variation in the ASD lymphoblasts, (3) use mitochondrial biochemistry and somatic cell genetics to demonstrate that the lymphoblasts manifest the mitochondrial defect predicted by the nDNA and/or mtDNA variants, and (4) confirm the presence of mitochondrial defects in selected mutant patients using non-invasive magnetic resonance spectroscopy (MRS) of muscle and brain, micro-organic breath analysis (MOBA), and the diffuse optical spectroscopy (DOS) of muscle. Demonstration that a subset of ASD patients harbor mitochondrial defects would suggest new approaches for the treatment of this class of ASD.

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To determine if a subset of autism spectrum (ASD) disease is caused by mitochondrial dysfunction, we propose to survey patient lymphoblastoid cell lines for those harboring nuclear DNA (nDNA) copy number variants (CNVs) or mitochondrial DNA (mtDNA) mutations that alter mitochondrial genes. Cell lines from the mutant patients will be tested for the expected mitochondrial function. If mitochondrial defects are found, selected patients will be tested using non-invasive biophysical and biochemical tools to determine if they manifest a functional mitochondrial defect.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZMH1-ERB-B (A1))
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Mamounas, Laura
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Children's Hospital of Philadelphia
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